1,3-Dioxolane-5-yl-hexenoic acid derivatives

ABSTRACT

The invention describes novel (2-styryl-, 2-naphthyl- and 2-phenethyl-4-o-hydroxyphenyl-1,3-dioxan-5-yl)alkenoic acids and related tetrazoles and sulphonamides, of the formula I wherein Q completes a benzene or pyridine ring, Y is vinylene, Z is carboxy, 1 (H)-tetrazol-5-yl or a group of the formula --CO.NHSO 2  R 6 , and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A 1 , A 2 , n and m have the meanings defined in the specification, and pharmaceutically acceptable salts thereof, for use in conjunction with their pharmaceutical compositions in treating certain pulmonary and/or vascular disorders. The invention also describes various processes and intermediates for the manufacture of the novel compounds.

This invention concerns novel alkene derivatives and, more particularly,novel (2-styryl-, 2-naphthyl- and2-phenethyl-4-o-hydroxyphenyl-1,3-dioxan-5-yl)alkenoic acids and relatedcompounds, which antagonise one or more of the actions of thromboxane A₂(hereafter referred to as "TXA₂ ") and which are of value as therapeuticagents.

It is known that TXA₂ is a potent aggregator of blood platelets and apowerful vasconstrictor. TXA₂ is also a potent constrictor of bronchialand tracheal smooth muscle. TXA₂ may therefore be involved in a widevariety of disease conditions, for example ischaemic heart disease suchas myocardial infarction, angina, cerebrovascular disease such astransient cerebral ischaemia, migraine and stroke, peripheral vasculardisease such as atherosclerosis, microangiopathy, hypertension and bloodclotting defects due to lipid imbalance, and pulmonary disease such aspulmonary embolism, bronchial asthma, bronchitis, pneumonia, dyspnoeaand emphysema. Accordingly, compounds which antagonise the actions ofTXA₂ may be expected to have therapeutic value in the prevention ortreatment of any one or more of the above mentioned diseases or anyother disease conditions in which it is desirable to antagonise theactions of TXA₂.

It is known that certain 4-phenyl-1,3-dioxan-5-ylalkenoic acids possessTXA₂ antagonist properties (European patent application, publication No.94239).

According to the invention there is provided a [2,4,5-cis]-dioxane ofthe formula I (set out hereinafter) wherein A¹ and A² are hydrogen ortogether form a direct link; R¹ and R² are independently hydrogen,(1-4C)alkyl or phenyl optionally bearing 1 or 2 substituentsindependently selected from halogeno, nitro, cyano, trifluoromethyl and(1-4C)alkyl; R³ is hydrogen or, together with A¹, forms vinylene,ethylene or oxymethythene; R⁴ and R⁵ are independently selected fromhydrogen, halogeno, (1-4C)alkyl, (1-4C)alkoxy, nitro, cyano,trifluoromethyl, hydroxy, (1-4C)alkanoylamino and (2-4C)alkanoyloxy, orR⁴ and R⁵ together form (1-4C)alkylenedioxy attached to adjacent carbonatoms on Q; Y is or vinylene; n is 1 or 2; m is 1, 2 or 3; Q, inconjunction with its adjoining carbon atoms (shown with an asterisk informula I hereinafter), completes a benzene or pyridine ring; and Z iscarboxy, 1(H)-tetrazol-5-yl or a group of the formula CO.NH.SO₂ R⁶wherein R⁶ is (1-6C)alkyl, benzyl or phenyl, the latter two of which mayoptionally bear a halogeno, (1-4C)alkyl, (1-4C)alkoxy, nitro, cyano ortrifluoromethyl substituent; or a pharmaceutically acceptable saltthereof.

The compounds of formula I contain at least three asymmetric carbonatoms and may exist and be isolated in racemic and optically activeforms. In addition, the compounds of formula I contain 1 or 2 exocyclicvinylene groups and may exist, and be isolated, in separatestereoisomeric forms (`E` and `Z`). It is to be understood that theinvention includes any racemic, optically active or stereoisomeric form,or mixture thereof, which is capable of antagonising one or more of theactions of TXA₂, it being well known in the art how to prepareindividual optical isomers (for example by synthesis from opticallyactive starting materials or resolution of a racemic form) andindividual `E` and `Z` stereoisomers (for example by synthesis fromappropriate starting materials or by chromatographic separation of amixture of isomers), and how to determine the TXA₂ antagonist propertiesusing the standard tests described hereafter.

A preferred value for n is 1 and for m is 2 or 3.

A particular value for R¹ or R² when it is (1-4C)alkyl is, for example,methyl or ethyl.

A particular value for R⁶ when it is (1-6C)alkyl is, for example,methyl, ethyl, propyl or isopropyl.

Particular values for optional substituents R⁴ and R⁵, or forsubstituents present as part of R¹, R² or R⁶ when they are optionallysubstituted phenyl or benzyl, as defined above, include, for example:

for halogeno: fluoro, chloro or bromo;

for (1-4C)alkyl: methyl or ethyl;

for (1-4C)alkoxy: methoxy or ethoxy;

for (1-4C)alkanoylamino: formamido or acetamido;

for (1-4C)alkylenedioxy: methylenedioxy or ethylenedioxy.

Two groups of compounds of the invention of particular interest comprisestyryl compounds of the formula IIa and naphthyl compounds of theformula IIb respectively, wherein R¹ and R² are independently hydrogenor (1-4C)alkyl, R⁴ and R⁵ are independently selected from hydrogen,halogeno (such as fluoro, chloro and bromo), (1-4C)alkyl (such asmethyl), (1-4C)alkoxy (such as methoxy), hydroxy, nitro, cyano andtrifluoromethyl, or R⁴ and R⁵ together form methylenedioxy; p is 2 or 3;and Z has the meanings given above; together with the pharmaceuticallyacceptable salts thereof.

It will be appreciated that the 2-styryl compounds of formula IIa mayexist in the `E` or `Z` stereoisomeric form. However, in general, the`E` 2-styryl stereoisomeric (or trans) form is preferred.

A preferred value for Z is, for example, carboxy. A preferred value forp is 2.

A preferred value for Y is cis-vinylene i.e. the `Z` sterioisomericform.

Specific compounds of the invention are described in the accompanyingExamples. However, illustrative compounds of particular interest are thecarboxylic acids described in Examples 1 and 7, or a pharmaceuticallyacceptable salt thereof.

Particular pharmaceutically acceptable salts of compounds of formula Iare, for example, alkali metal and alkaline earth metal salts, such aslithium, sodium, potassium, magnesium and calcium salts, aluminium andammonium salts, and salts with organic amines and quaternary bases,forming physiologically acceptable cations, such as salts withmethylamine, dimethylamine, trimethylamine, ethylenediamine, piperidine,morpholine, pyrrolidine, piperazine, ethanolamine, triethanolamine,N-methylglucamine, tetramethylammonium hydroxide andbenzyltrimethylammonium hydroxide.

The compounds of formula I may be manufactured by conventionalprocedures of organic chemistry well known in the art for themanufacture of structurally analogous compounds. Such procedures areprovided as a further aspect of the invention and are illustrated by thefollowing processes in which R¹, R², R³, R⁴, R⁵, R⁶, A¹, A², Q, Y, Z, n,m and p have any of the meanings herein above:

(a) An aldehyde of the formula III is reacted with a Witting reagent ofthe formula IVa, IVb or IVc wherein R' is (1-6C)alkyl or aryl(especially phenyl) and M⁺ is a cation, for example an alkali metalcation, such as the lithium, sodium or potassium cation.

The process in general produces compounds of formula I in which thesubstituents adjacent to the double bond have predominantly cis-relativestereochemistry i.e. the `Z` isomer. However the compounds of formula Ihaving trans-relative stereochemistry may also be obtained from theprocess by conventional separation of the mixture of cis- andtrans-isomers first obtained.

The process is conveniently performed in a suitable solvent or diluent,for example an aromatic solvent such as benzene, toluene orchlorobenzene, an ether such as 1,2-dimethoxyethane, t-butyl methylether, dibutyl ether or tetrahydrofuran, in dimethyl sulphoxide ortetramethylene sulphone, or in a mixture of one or more such solvents ordiluents. The process is generally performed at a temperature in therange, for example, -80° C. to 40° C., but is conveniently performed ator near room temperature, that is in the range 0° to 35° C.

(b) For a compound of formula I wherein Z is 1(H)-tetrazol-5-yl, anitrile of the formula V is reacted with an azide.

A particularly suitable azide is, for example, an alkali metal azidesuch as sodium or potassium azide, preferably together with an ammoniumhalide, for example ammonium chloride, ammonium bromide ortriethylammonium chloride. The process is preferably carried out in asuitable polar solvent, for example N,N-dimethylformamide orN-methylpyrrolidone and, conveniently, at a temperature in the range,for example, 50° to 160° C.

(c) A phenol derivative of the formula VI, wherein R" is a suitableprotecting group, for example (1-6C)alkyl (such as methyl or ethyl),acyl (such as acetyl, benzoyl, methanesulphonyl or p-toluene-sulphonyl),allyl, tetrahydropyran-2-yl or trimethylsilyl, is deprotected.

The precise deprotection conditions used depend on the nature of theprotecting group R". Thus, for example, when it is methyl or ethyl thedeprotection may be carried out by heating the sodium thioethoxide in asuitable solvent (such as N,N-dimethylformamide or1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone) at a temperature inthe range, for example, 60°-160° C. Alternatively, an ethyl or methylprotecting group may be removed by reaction with lithiumdiphenylphosphide in a suitable solvent (such as tetrahydrofuran ort-butyl methyl ether) at a temperature in the range, for example, 0°-60°C. When the protecting group is acyl it may be removed, for example, byhydrolysis in the presence of a base (such as sodium or potassiumhydroxide) in a suitable aqueous solvent [such as an aqueous(1-4C)alkanol] at a temperature in the range, for example, 0°-60° C.When the protecting group is allyl or tetrahydropyran-2-yl it may beremoved, for example, by treatment with strong acid such astrifluoroacetic acid and when it is trimethylsilyl, it may be removed,for example, by reaction with aqueous tetrabutylammonium fluoride orsodium fluoride, using a conventional procedure.

(d) An erythro-diol derivative of the formula VII, wherein one of Q¹ andQ² is hydrogen and the other is hydrogen or a group of the formula--CRaRb.OH (wherein Ra and Rb are the same or different (1-4C)alkyl), isreacted with an aldehyde of the formula IX, or an acetal, hemiacetal orhydrate thereof.

The aldehyde of formula IX [or its hydrate, or its acetal or hemiacetalwith a (1-4C)alkanol (such as methanol or ethanol] is generally used inexcess.

The reaction is generally performed in the presence of an acid catalyst,such as hydrogen chloride, hydrogen bromide, sulphuric acid, phosphoricacid, methanesulphonic acid, p-toluenesulphonic acid, or an acidicresin, conveniently in the presence of a suitable solvent or diluent,such as toluene, xylene or an ether, for example tetrahydrofuran,dibutyl ether, methyl t-butyl ether or 1,2-dimethoxyethane, and attemperature in the range, for example 0° to 80° C.

Those starting materials of formula VII wherein Q¹ and Q² are bothhydrogen may be obtained, for example, by mild acid catalysed hydrolysisor alcoholysis of the dioxane ring of a compound of formula VIII whereinRa and Rb are both alkyl, such as methyl or ethyl. The hydrolysis oralcoholysis will normally be carried out a temperature in the range 10°to 80° C. using an aqueous mineral acid such as hydrochloric acid, in analkanol (such as ethanol or 2-propanol) or an ether (such astetrahydrofuran), as solvent.

The starting materials of formula VII wherein one of Q¹ and Q² ishydrogen and the other is a group of the formula --CRaRb.OH areintermediates in the above-mentioned formation of the starting materialsof formula VII, wherein Q¹ and Q² are both hydrogen. However, saidintermediates are not normally isolated or characterised. Accordingly,the invention also provides a modification of process (d) whichcomprises reacting a compound of formula VIII wherein one of Ra and Rbis hydrogen, methyl or ethyl and the other is methyl or ethyl, with anexcess of an aldehyde of the formula IX, or an acetal, hemiacetal orhydrate thereof, in the presence of an acid-catalyst (such as one ofthose given above), conveniently at a temperature in the range, forexample, 10° to 80° C. and optionally in the presence of a suitablesolvent or diluent (such as one of those given above).

The starting materials for use in the above processes may be made bygeneral procedures of organic chemistry, known for the preparation ofstructurally related compounds, for example by analogy with thoseprocedures disclosed in European patent application, publication No.94239.

The nitriles of formula V may be obtained, for example, by substitutingthe appropriate ylid of the formula R'₃ P═CH.(CH₂)_(m).CN for the ylidof formula IV in the Wittig reaction described in process (a) above. Theprotected phenol derivatives of formula VI may be made, for example, byusing an analogous procedure to process (a) above, using an aldehydeanalogous to formula III but wherein the phenol group has been protectedwith the group R". The starting materials of formula VIII may beobtained using analogous procedures to those described in Europeanpatent application, publication No. 94239.

The necessary Wittig reagents of formula IV may be obtained byconventional procedures, for example by treating the correspondingphosphonium halides with a strong base, such as sodium hydride, lithiumdiisopropylamide, potassium t-butoxide or butyllithium. They aregenerally formed in situ just prior to carrying out the condensationprocess (a) above.

It will be understood that the compounds of formula I wherein Z iscarboxy may also be obtained by other conventional procedures well knownin the art for the production of carboxylic acids, for example bybase-catalysed hydrolysis of the corresponding esters, for example, thelower alkyl esters. Such procedures are included within the invention.

When a compound of formula I wherein Z is a group of the formulaCO.NH.SO₂ R⁶ is required, one of the above procedures (a), (c) or (d) isperformed using the appropriate starting material of formula IVc, VI,VII or VIII.

The necessary starting materials of formula VI may conveniently beobtained by reacting the correponding protected acid of formula VIwherein Z is carboxy with a sulphonamide of the formula H₂ N.SO₂ R⁶ anda suitable dehydrating agent, for example dicyclohexylcarbodiimide,optinally together with an organic base, for example4-dimethylaminopyridine, in the presence of a suitable solvent ordiluent, for example methylene chloride at a temperature in the range,10°-50° C., but preferably at or near room temperature. Alternatively, areactive derivative of the compound of formula VI wherein Z is carboxy,for example an acid halide (such as the acid chloride) may be reactedwith an alkali metal salt (such as the sodium salt) of the appropriatesulphonamide, conveniently at or near room temperature and in a suitablesolvent or diluent, for example an ether, N,N-dimethylformamide ormethylene chloride.

When a salt of a compound of formula I is required, it may be obtainedby reaction with the appropriate base affording a physiologicallyacceptable cation, or by any other conventional procedure.

Further, when an optically active form of a compound of formula I isrequired, one of the aforesaid processes is carried out using anoptically active starting material. Alternatively, the racemic form of acompound of formula I may be reacted with an optically active form of asuitable organic base, for example ephedrine,N,N,N-trimethyl(1-phenylethyl)ammonium hydroxide or 1-phenylethylamine,followed by conventional separation of the diastereoisomeric mixture ofsalts thus obtained, for example by fractional crystallisation from asuitable solvent, for example a (1-4C)alkanol, whereafter the opticallyactive form of said compound of formula I may be liberated by treatmentwith acid using a conventional procedure for example using an aqueousmineral acid such as dilute hydrochloric acid.

Many of the intermediates defined herein are novel, for example thephenol derivatives of formula VI, and are provided as further separatefeatures of the invention.

As stated earlier, the compounds of formula I are antagonists of one ormore of the actions of TXA₂, for example certain of its actions on bloodplatelets, the vasculature and/or the lung. The antagonism may bedemonstrated in one or other of the following standard tests:

(a) The rabbit aortal strip model devised by Piper and Vane (Nature,1969, 223, 29-35) using as agonist a freshly prepared sample of TXA₂,generated by addition of arachidonic acid (25 μg) to citrated, plateletrich rabbit plasma (250 μg) and allowing the mixture to aggregate fullyover 90 seconds before use; alternatively the TXA₂ mimetic agent knownas U46619 (described by R. L. Jones et alia, in "Chemistry, Biochemistryand Pharmacological Activity of Prostanoids" edited by S. M. Roberts andF. Scheinmann, at page 211, Pergamon Press, 1979) may be used as theagonist;

(b) a blood platelet aggregation test based on that described by Born(Nature, 1962, 194, 927-929) and involving:

(i) aggregating human, citrated platelet-rich plasma by addition of theTXA₂ mimetic agent U46619 so that a dose-response curve is generated;

(ii) generating a dose-response curve for U46619 stimulated plateletaggregation in the presence of increasing amounts of test compound(generally in the range, 10⁻⁵ M to 10⁻¹⁰ M); and

(iii) calculating a K_(B) value indicating potency of TXA₂ antagonismfor the test compound, averaged over several concentrations, from thecalculated 50% response value for U46619 aggregation in the presence andabsence of test compound; and

(c) a bronchoconstriction test involving measuring the inhibition bytest compound of the bronchoconstriction induced in the Konzett-Rossler,anaesthetised guinea-pig model (as modified by Collier and James, Brit.J. Pharmacol., 1967, 30, 283-307) by intravenous administration of theTXA₂ mimetic agent, U46619 and involving:

(i) obtaining a cumulative dose-response curve to U46619 inducedbronchoconstriction by intravenous administration of constant volumes ofincreasing concentrations of U46619 (0.2-4 μg/kg) in physiologicalsaline solution and expressing bronchoconstriction as the maximum ofthat theoretically obtainable with no air flow to the test animal;

(ii) generating a cumulative dose-response curve to U46619 inducedbronchoconstriction at 30 minute intervals for 3 hours after oral dosingof test compound; and

(iii) calculating a dose-ratio for the test compound (that is the ratioof concentration of U46619 required to cause 50% bronchoconstriction inthe presence and absence of test compound) indicating the potency ofTXA₂ antagonism.

The antagonism of the effects of TXA₂ on the vasculature may bedemonstrated, for example, in rats in the following manner:

Male rats (Alderley Park strain) are anaesthetised with sodiumpentobarbital and blood pressure is monitored at the carotid artery. TheTXA₂ mimetic agent U46619 is administered intravenously via the jugularvein at 5 μg/kg to induce a 20-30 mm Hg (2640-3970 pascal) increase insystolic blood pressure. The process is repeated twice to establishreproducibility of response. A test compound is then administered eitherintravenously via the jugular vein or orally via a cannula directly intothe stomach and the or animal challenged with U46619 five minutes afterdosing with test compound and then successively every ten minutes untilthe hypertensive effect of U46619 is no longer blocked. Further, theantagonism of the effects of TxA₂ in vivo may be demonstrated, forexample, by assessing the effects of a test compound on the aggregationof blood platelets obtained after administration of test compound to atest animal such as a rabbit, rat, guinea pig or dog, using standardprocedures similar to that described in (a) above. However, when theaggregation of dog platelets is being studied it is necessary to use apre-determined, threshold concentration of the platelet aggregrantadenosine diphosphate (about 0.4-1.2×10⁻⁶ M) together with the TxA₂mimetic agent, U46619.

By way of illustration, the compound described in Example 1 hereafterpossesses a pA₂ of 8.9 in procedure (a) (U46619) and exhibits a K_(B) of1.2×10⁻⁸ M in procedure (b) above.

In general, compounds of formula I show significant TxA₂ antagonistproperties in one or more of the above mentioned tests i.e. test (a)pA₂ >6.0; test (b) K_(B) >5×10⁻⁶ ; test (c) dose ratio>5 at 100 μg/kgp.o. In addition compounds of formula I may show significant activity inthe rat blood pressure test and/or in one or more of the ex vivo bloodplatelet tests referred to above. No significant adverse effects havebeen observed at the active doses in vivo.

As stated previously, the compounds of formula I may be used in thetherapy or prevention of diseases or adverse conditions in warm-bloodedanimals in which it is desirable to antagonise one or more of theactions of TXA₂. In general, a compound of formula I will beadministered for this purpose by an oral, rectal, intravenous,subcutaneous, intramuscular or inhalation route, so that a dose in therange, for example 0.01-5 mg/kg body weight, will be given up to fourtimes per day, varying with the route of administration, the severity ofthe condition and the size and age of the patient under treatment.

The compounds of formula I will generally be used in the form of apharmaceutical composition comprising a compound of formula I or apharmaceutically acceptable salt thereof as defined hereinbefore,together with a pharmaceutically acceptable diluent or carrier. Such acomposition is provided as a further feature of the invention and may bein a variety of dosage forms. For example, it may be in the form oftablets, capsules, solutions or suspensions for oral administration; inthe form of a suppository for rectal administration; in the form of asterile solution or suspension for administration by intravenous orintramuscular injection; in the form of an aerosol or a nebulisersolution or suspension, for administration by inhalation; and in theform of a powder together with pharmaceutically acceptable inert soliddiluents such as lactose, for administration by insufflation.

The pharmaceutical compositions may be obtained by conventionalprocedures using pharmaceutically acceptable diluents and carriers wellknown in the art. Tablets and capsules for oral administration mayconveniently be formed with an enteric coating, for example comprisingcellulose acetate phthalate, to minimise contact of the activeingredient of formula I with stomach acids.

The pharmaceutical compositions of the invention may also contain one ormore agents already known to be of value in the diseases or conditionsintended to be treated; for example a known platelet aggregationinhibitor, hypolipidemic agent, anti-hypertensive agent, beta-adrenergicblocker or a vasodilator may usefully also be present in apharmaceutical composition of the invention for use in treating a heartor vascular disease or condition. Similarly, by way of example, ananti-histamine, steroid (such as beclomethasone dipropionate), sodiumcromoglycate, phosphodiesterase inhibitor or a beta-adrenergic stimulantmay usefully also be present in a pharmaceutical composition of theinvention for use in treating a pulmonary disease or condition.

In addition to their use in therapeutic medicine, the compounds offormula I are also useful as pharmacological tools in the developmentand standardisation of test systems for the evaluation of the effects ofTXA₂ in laboratory animals such as cats, dogs, rabbits, monkeys, ratsand mice, as part of the search for new therapeutic agents. Thecompounds of formula I may also be used because of their TXA₂ antagonistproperties in helping to maintain the viability of blood and bloodvessels in warm-blooded animals (or parts thereof) under-goingartificial extracorporeal circulation, for example during limb or organtransplant. When used for this purpose a compound of formula I, or aphysiologically acceptable salt thereof, will generally be administeredso that a steady state concentration in the range, for example, 0.1 to10 mg per liter is achieved in the blood.

The invention will now be illustrated by the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo;

(ii) operations were carried out at room temperature, that is in therange 18°-26° C.;

(iii) flash column chromatography was performed on Merck Kieselgel 60(Art. 9385), monitoring the process by thin layer chromatography onMerck 0.25 mm Kieselgel 60F 254 plates (Art. 5715); these materials wereobtained from E. Merck, Darmstadt, W. Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable;

(v) NMR spectra were normally determined at 200 MHz in CDCl₃ usingtetramethylsilane (TMS) as an internal standard, and expressed aschemical shifts (delta values) in parts per million relative to TMSusing the following abbreviations for designation of major peaks; s,singlet; m, multiplet; t, triplet; br, broad; d, doublet; when a singlechemical shift value is given for a multiplet (m) this corresponds tothe centre point of the signals making up the multiplet; and

(vi) end-products were isolated as racemates, and characterised by NMR,microanalysis, mass spectroscopy and/or other standard procedures.

EXAMPLE 1

Sodium hydride (262 mg, 50% w/w dispersion in mineral oil) was added toa stirred suspension of4(Z)-6-([2,4,5-cis]-4-o-methoxyphenyl-2(E)-styryl-1,3-dioxan-5-yl)hexenoicacid (370 mg) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone(DMPU) (10 ml), maintained at 0°-5° C. After 3 minutes, ethanethiol(0.42 ml) was added and the mixture heated to 90° C. for 6 hours. Thecooled mixture was diluted with water (15 ml) and washed with methylenechloride (2×25 ml). The aqueous phase was acidified to pH4 with aceticacid and extracted with diethyl ether (4×30 ml). The extracts were dried(MgSO₄) and evaporated. The oil thus obtained was purified by flashcolumn chromatography on silica, eluting with toluene/ethylacetate/acetic acid (91:9:2, by volume) to give4(Z)-6-([2,4,5-cis]-4-o-hydroxyphenyl-2(E)-styryl-1,3-dioxan-5-yl)hexenoicacid as a crystalline solid, m.p. 138°-141° C.; NMR: 1.71 (1H, d), 1.93(1H, d), 2.32 (4H, s), 2.72 (1H, m), 4.04 (1H, d), 4.18 (1H, d), 5.38(3H, m), 6.27 (1H, dd), 7.17 (10H, m) and 7.92 (1H, s); m/e 394 (M⁺).

The starting material was obtained as follows:

(E)-Cinnamaldehyde (0.41 ml) and p-toluenesulphonic acid (5 mg) wereadded to a solution of4(Z)-6-(4-o-methoxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl)hexenoic acid(A) (700 mg) in toluene (15 ml). The mixture was stirred and heatedunder reflux for 1.5 hours. The cooled reaction mixture was purified byflash column chromatography on silica, eluting with toluene/ethylacetate/acetic acid (90:10:2, by volume), to give4(Z)-6-([2,4,5-cis]-4-o-methoxyphenyl-2(E)-styryl-1,3-dioxan-5-yl)hexenoicacid (455 mg, 53%); NMR: 1.66 (1H, m), 1.9 (1H, m), 2.27 (4H, m), 2.52(1H, m), 3.8 (3H, m), 4.08 (2H, m), 5.3 (4H, m), 6.3 (1H, dd), 6.9 (3H,m) and 7.41 (7H, m); m/e 409 (M⁺ +H).

The starting acid (A) was obtained as follows:

Potassium t-butoxide (12.3 g) was added over 2 minutes to a stirredsuspension of (3-carboxypropyl)triphenylphosphonium bromide (23.6 g) intetrahydrofuran (THF) (230 ml) at 0°-5° C. The mixture was stirred atambient temperature for 30 minutes and cooled to 0° C. before theaddition of(4-o-methoxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl)acetaldehyde (5.9 g)during 5 minutes. The mixture was stirred for 45 minutes and water (50ml) was added. The solvent was removed by evaporation. The residue wasdissolved in water (250 ml). The solution obtained was washed with ethylacetate (3×100 ml) and acidified to pH 4 with acetic acid. The liberatedoil was extracted with ethyl acetate (3×100 ml). The extracts werewashed with saturated brine (2×100 ml), dried (MgSO₄) and evaporated togive an oil. The oil was purified by flash column chromatography onsilica, eluting with toluene/ethyl acetate/acetic acid (80:20:1, byvolume), to give 4(Z)-6-(4-o-methoxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl)hexenoic acid (A)as a colourless solid (6.0 g, 82%) m.p. 92°-96° C.; NMR: 1.65 (8H, m),2.35 (5H, m), 3.85 (5H, m), 5.28 (3H, m) and 7.1 (4H, m).

EXAMPLES 2-4

Using a similar procedure to that described in Example 1, but startingfrom the appropriate o-methoxyphenyl derivative of formula X, thefollowing acids of formula XI were obtained in yields of 28-80%:

    ______________________________________                                                            m.p.     partial NMR                                      EXAMPLE  R          (°C.)                                                                           Data                                             ______________________________________                                        2        PhCH.sub.2 CH.sub.2                                                                      126-128  2.08 (2H,m), 2.8 (2H,m),                                                      4.75 (1H,t), 6.87 (3H,m)                                                      7.2 (7H,m).                                      3        2-Naphthyl 44-46    6.87 (2H,m), 7.05                                                             (2H,m), 7.17 (1H,m),                                                          7.49 (2H,m), 7.65                                                             (1H,dd), 7.85 (4H,m),                                                         8.0 (1H,s).                                      4        PhCH═C.Me                                                                            oil*     1.65 (3H,dd), 3.66                                                            (2H,m), 4.95 (4H,m),                                                          6.5 (3H,m), 6.85 (7H,m).                         ______________________________________                                         Note:                                                                         *1:1 mixture of `E` and `Z` stereoisomers                                

The following starting materials of formula X were obtained using asimilar procedure to that described in Example 1, but starting from theappropriate aldehyde of the formula R.CHO and were obtained in yields of33-92%:

    ______________________________________                                                         partial NMR                                                  R         State  Data                                                         ______________________________________                                        PhCH.sub.2 CH.sub.2                                                                     oil    2.05 (2H,m), 2.85 (2H,q), 3.8 (3H,s),                                         4.81 (1H,t), 6.82 (1H,d), 6.98 (1H,m),                                        7.23 (7H,m), 7.43 (1H,m).                                    2-Naphthyl                                                                              oil    3.84 (3H,s), 5.92 (1H,s), 7.92 (2H,m),                                        7.23 (2H,m), 7.48 (3H,m), 7.72 (1H,m),                                        7.87 (3H,m), 8.02 (1H,s).                                    PhCH═C.Me                                                                            oil*  2.05 (3H,dd), 3.0 (1H,m), 3.83 (3H,d),                                        5.35 (4H,m), 6.7 (H,m), 6.93 (4H,m),                                          7.31 (7H,m).                                                 ______________________________________                                         Note:                                                                         *Obtained an a 1:1 mixture of `E` and `Z` stereoisomers.                 

EXAMPLE 5

4-Cyano-(E)-cinnamaldehyde (150 mg), p-toluene sulphonic acid (3 mg) and4(Z)-erythro-8-hydroxy-7-hydroxymethyl-8-o-methoxyphenyl-4-octenoic acid(294 mg) were stirred in toluene (3 ml) for 18 hours and then purifiedby flash column chromatography on silica. Elution with methylenechloride/ethanol (96:4, by volume), evaporation and crystallisation ofthe residue from n-hexane/ethyl acetate (50:50, by volume) gave as acolourless solid4(Z)-6-([2,4,5-cis]-2-[4-cyano-(E)-styryl]-4-o-methoxyphenyl-1,3-dioxan-5-yl)hexenoicacid (110 mg, 25%) m.p. 154°-156° C.; NMR: 3.82 (3H, s), 5.3 (4H, m),6.4 (1H, dd), 6.83 (1H, d), 6.89 (1H, d), 6.97 (1H, m), 7.25 (1H, m) and7.55 (5H, m); m/e 433 (M+).

The necessary starting material was obtained as follow:

A solution of A (4.20 g) in a mixture of water (12 ml), 2M hydrochloricacid (0.5 ml) and THF (40 ml) was heated with stirring at 60°-70° C.After 2 hours the mixture was cooled to ambient temperature and pouredinto water (100 ml). The aqueous mixture was extracted with ether (3×50ml). The combined extracts were washed successively with water (2×40 ml)and saturated brine (40 ml), then dried (MgSO₄) and evaporated to give4(Z)-erythro-8-hydroxy-7-hydroxymethyl-8-o-methoxyphenyl-4-octenoic acidas a colourless oil (3.80 g); NMR: 1.95 (1H, m), 2.11 (1H, m), 2.37 (5H,m), 3.67 (2H, m), 3.83 (3H, s), 4.84 (3H, br), 5.22 (1H, d, J=4 Hz),5.38 (2H, m), 6.88 (1H, br d J=7 Hz), 6.98 (1H, bt J=7 Hz), 7.25 (1H, tdJ=7, 1.5 Hz), 7.42 (1H, dd J=7, 1.5 Hz).

EXAMPLE 6

2-Nitro-(E)-cinnamaldehyde (107 mg) and p-toluene sulphonic acid (2 mg)were added to a stirred suspension of4(Z)-6-(4-o-hydroxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl)hexenoic acid(161 mg) in toluene (2 ml). The mixture was stirred for 3 hours and thenpurified by flash column chromatography on silica, eluting withtoluene/ethyl acetate/acetic acid (92:8:2, by volume), to give4(Z)-6-([2,4,5-cis]-4-o-hydroxyphenyl-2-[2-nitro-(E)-styryl]-1,3-dioxan-5-yl)hexenoicacid, as a pale yellow solid (156 mg, 71%), m.p. 148°-150° C.; NMR: 1.85(2H, m), 2.4 (4H, m), 2.65 (1H, m), 4.12 (2H, m), 5.38 (4H, m), 6.25(1H, dd), 6.86 (2H, m), 7.13 (2H, m), 7.45 (2H, m), 7.65 (2H, m) and7.96 (1H, dd); m/e 440 (M⁺ +H).

The hexenoic acid starting material was obtained as follows:

Sodium hydride (432 mg. 50% w/w dispersion in mineral oil) was added toa stirred solution of4(Z)-6-(4-o-methoxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl)-hexenoicacid (500 mg) in DMPU (7.5 ml) at 0°-5° C. After 5 minutes, ethanethiol(0.66 ml) was added dropwise during 3 minutes. The mixture wasmaintained at 0°-5° C. for 10 minutes and then heated at 135°-140° C.for 50 minutes. The cooled reaction mixture was diluted with water (15ml) and then washed with methylene chloride (2×30 ml). The aqueous phasewas acidified to pH 4 with acetic acid and extracted with diethyl ether(4×30 ml). The ether extracts were dried (MgSO₄) and evaporated. The oilobtained was purified by flash column chromatography on silica, elutingwith toluene/ethyl acetate/acetic acid (80:20:2, by volume), to give4(Z)-6-(4-o-hydroxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl)hexenoicacid, as a colourless solid (95 mg, 31%), m.p. 85°-89° C.; NMR: 1.6 (7H,m), 1.82 (1H, m), 2.32 (5H, m), 2.7 (1H, m), 3.83 (1H, dd), 4.12 (1H,gg), 5.24 (3H, m), 6.88 (3H, m), 7.17 (2H, m) and 8.47 (1H, s); m/e: 320(M⁺).

EXAMPLES 7-10

Using a similar procedure to that described in Example 6, but startingfrom the appropriate aldehyde the following hexenoic acids of formula XIwere obtained in yields of 15-70%

    ______________________________________                                        EX-                 m.p.      partial NMR                                     AMPLE  R            (°C.)                                                                            Data                                            ______________________________________                                        7      2- -o-cyanophenyl-                                                                         113-116   5.45 (4H,m), 6.43                                      (E)-vinyl              (1H,dd), 6.84 (2H,m)                                                          7.03 (1H,m), 7.18                                                             (3H,m), 7.37                                                                  (1H,m), 7.62 (3H,m).                            8      4- -p-cyanophenyl-                                                                         135-137   5.37 (4H,m), 6.35                                      (E)vinyl               (1H,dd), 6.86                                                                 (3H,m), 7.0 (1H,m),                                                           7.15 (1H,m), 7.55                                                             (4H,q).                                         9      2,2-diphenyl-                                                                              52-56     5.1 (1H,d), 5.4,                                       vinyl                  (3H,m), 6.16 (1H,d)                                                           6.86 (3H,m), 7.37                                                             (11,m).                                         10     1-methyl-2-  oil*      1.65 (3H,dd), 3.66                                     phenylvinyl            (2H,m), 4.95                                                                  (4H,m), 6.5 (3H,m)                                                            6.85 (7H,m).                                    ______________________________________                                         Note:                                                                         *1:1 mixture of `E` and `Z` stereoisomers                                

The starting material 2-cyano-(E)-cinnamaldehyde used in Example 7 wasprepared as follows:

A solution of lithium (77 mg) in methanol (30 ml) was added during 2hours to a stirred suspension of 2-cyanobenzaldehyde and(1,3-dioxolan-2-yl-methyl)-triphenyl phosphonium bromide (4.71 g) indimethylformamide (34 ml) at 85° C. The mixture was stirred at 85° C.for 6 hours, allowed to cool and poured into water (450 ml). Thereaction mixture was extracted with diethyl ether (3×120 ml) and thecombined ether extracts washed with saturated brine, dried (MgSO₄) andevaporated. The residue was dissolved and stirred in tetrahydrofuran (30ml) and 3M hydrochloric acid (30 ml) for 2 hours. The mixture wasdiluted with water (100 ml) and extracted with diethyl ether (300 ml).The ether was washed with saturated sodium hydrogen carbonate solution(2×50 ml) and saturated brine, dried (MgSO₄) and evaporated. The residuewas purified by flash column chromatography on silica, eluting withn-hexane/ethyl acetate (80:20:, by volume) to give as a pale yellowsolid 2-cyano-(E)-cinnamaldehyde (504 mg, 45%) m.p. 107°-110° C.; NMR:6.82 (1H, q), 7.69 (5H, m) and 9.81 (1H, d); m/e 157 (M+).

EXAMPLE 11

Illustrative pharmaceutical dosage forms include the following tabletand capsule formulations, which may be otained using standardprocedures:

    ______________________________________                                                            mg/tablet                                                 ______________________________________                                        TABLET I                                                                      Compound X*           5.0                                                     Lactose Ph. Eur       89.25                                                   Croscarmellose sodium 4.0                                                     Maize starch paste (5% w/v paste)                                                                   0.75                                                    Magnesium stearate    1.0                                                     TABLE II                                                                      Compound X*           50                                                      Lactose Ph. Eur       223.75                                                  Croscarmellose sodium 6.0                                                     Maize starch          15.0                                                    Polyvinylpyrrolidone (5% w/v paste)                                                                 2.25                                                    Magnesium stearate    3.0                                                     CAPSULE                                                                       Compound X*           10                                                      Lactose Ph. Eur       488.5                                                   Magnesium stearate    1.5                                                     ______________________________________                                         Note:                                                                         Compound X* stands for a compound of formula I, or a salt thereof, for        example a compound of formula I described in any of the previous Examples

    ______________________________________                                                                Formulae                                                                      (Description)                                         ______________________________________                                         ##STR1##                     I                                                ##STR2##                     IIa                                              ##STR3##                     IIb                                              ##STR4##                     III                                             R.sub.3 'PCH.(CH.sub.2).sub.m.CO.sub.2.sup.⊖ M.sup.⊕                                            IVa                                              ##STR5##                     IVb                                              ##STR6##                     IVc                                              ##STR7##                     V                                                ##STR8##                     V                                                ##STR9##                     VII                                              ##STR10##                    VIII                                             ##STR11##                    IX                                               ##STR12##                    X                                                ##STR13##                    XI                                              ______________________________________                                    

What we claim is:
 1. A ( 2,4,5-cis)-dioxane of the formula I ##STR14##wherein A¹ and A² are hydrogen or together form a direct link; R¹ and R²are hydrogen; R³ is hydrogen; R⁴ and R⁵ are independently selected fromhydrogen, halogeno, (1-4C)alkyl, (1-4C)alkoxy, nitro, cyano,trifluoromethyl, hydroxy, (1-4C)alkanoylamino and (2-4C)alkanoyloxy, orR⁴ and R⁵ together form (1-4C)alkylenedioxy attached to adjacent carbonatoms in Q when the latter completes a benzene ring; Y is cis-vinylene;n is 1; m is 2; Q, in conjunction with its adjoining carbon atoms,completes a benzene or pyridine ring; and Z is carboxy,1(H)-tetrazol-5-yl or a group of the formula --CO.NH.SO₂ R⁶ wherein R⁶is (1-6C)alkyl, benzyl or phenyl, the latter two of which areunsubstituted or bear a halogeno, (1-4C)alkyl, (1-4C)alkoxy, nitro,cyano or trifluoromethyl substituent; or a pharmaceutically acceptablesalt thereof.
 2. A compound as claimed in claim 1 wherein; R⁴ and R⁵ areindependently selected from hydrogen, fluoro, chloro, bromo, methyl,ethyl, methoxy, ethoxy, nitro, cyano, trifluoromethyl, hydroxy,formamido, acetamido, acetoxy and propionyloxy, or R⁴ and R⁵ togetherform methylenedioxy or ethylenedioxy attached to adjacent carbon atomson Q when Q completes a benzene ring; and R⁶ is methyl, ethyl, propyl,isopropyl, benzyl or phenyl, the latter two of which are unsubstitutedor bear a fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, nitro,cyano or trifluoromethyl substituent.
 3. A styryl compound of theformula IIa ##STR15## wherein R¹ and R² are hydrogen or; R⁴ and R⁵ areindependently selected from hydrogen, halogeno, (1-4C)alkyl,(1-4C)alkoxy, hydroxy, nitro, cyano and trifluoromethyl, or R⁴ and R⁵together form methylenedioxy; p is 2; and Z has the meaning defined inclaim 1; or a pharmaceutically acceptable salt thereof.
 4. A compound asclaimed in claim 1 wherein Z is carboxy.
 5. A compound selected from4(Z)-6-([2,4,5-cis]-4-o-hydroxy-phenyl-2(E)-styryl-1,3-dioxan-5-yl)hexenoicacid,4(Z)-6-(2,4,5-cis]-2(E)-[2-cyanostyryl]-4-o-hydroxyphenyl-1,3-dioxan-5yl)hexenoicacid and the pharmaceutically acceptable salts thereof.
 6. A salt asclaimed in claim 1 or 3 which is selected from alkali metal, alkalineearth metal, aluminium and ammonium salts, and from salts with organicamines and quaternary bases, forming physiologically acceptable cations.7. A method of antagonising one or more of the actions of thromboxane A₂in a warm-blooded animal requiring such treatment which comprisesadministering to the said animal an effective amount of a compound or apharmaceutically acceptable salt thereof, as defined in claim 1 or
 3. 8.A pharmaceutical composition for use in antagonising one or more of theactions of thromboxane A₂ in a warm-blooded animal which comprises aneffective amount of a compound, or a pharmaceutically acceptable saltthereof, as claimed in claim 1 or 3 together with a pharmaceuticallyacceptable diluent or carrier.